The binding of insulin to its cell surface receptor initiates a cascade of cell signaling, which involves the activation of phosphatidyl inositol 3-kinase (PI3K) via the insulin receptor substrates (IRS) (FIG. 1). PI3K in turn activates the enzyme AKT, leading to the translocation of glucose transporters (Glut4) to cell surface. Glucose transporters bring glucose inside a cell. A defect in cellular uptake of glucose can lead to accumulation of glucose outside a cell (in circulation), leading to a hyperglycemic or diabetic state. In contrast, increasing cellular glucose uptake can clear it from the circulation, thus improving hyperglycemia or diabetes.
Ad36 is a human adenovirus that increases adiposity in experimentally infected animals, yet improves their glycemic control (1, 2). In humans, natural infection with Ad36 is associated with better glycemic control (1). Cell signaling studies have shown that Ad36 up-regulates PI3K activation, not via the conventional insulin-IRS pathway, but instead via activating Ras (FIG. 1), which leads to enhanced uptake of glucose in adipocytes and myocytes (3-5). In adipocytes and their progenitors, Ad36 up-regulates PPARγ, a key gene that initiates adipogenesis, which leads to a greater differentiation of fat cells, and lipid accumulation, and consequentially, greater adiposity (6, 7). On the other hand, Ad36 increases glucose uptake in adipose tissue and adipocytes (8). Thus, Ad36 possesses the dual property of increasing adiposity, yet improving glycemic control.
The adipogenic and glycemic effects of Ad36 are mediated via its E4orf1 protein, which up-regulates PPARγ, increases adiposity and increases cellular glucose uptake (9, 10). Up-regulation of PPARγ is also associated with improved glycemic control. The thiazolidinedione (TZD) class of anti-diabetic drugs up-regulate PPARγ and improve glycemic control, while also increasing adiposity (11, 12). The dual action of Ad36 or its E4orf1 protein is similar to that of the thiazolidinedione (TZD) drugs. Unfortunately, excess adiposity is associated with poor health and glycemic control.
Many AKT inhibitors are known in the art and have been suggested for cancer therapy. (Lindsley, C. W., Curr. Topics in Med. Chem., 10(4):458-477 (2010).)
Thus a need exists for new therapies that are able to improve glycemic control independent of adipogenesis.